A. Cell Mediated Immune Responses
The immune system of humans and other mammals is responsible for providing protection against infection and disease. Such protection is provided both by a humoral immune response and by a cell-mediated immune response. The humoral response results in the production of antibodies and other biomolecules that are capable of recognizing and neutralizing foreign targets (antigens). In contrast, the cell-mediated immune response involves the activation of macrophages, natural killer cells (NK), and antigen-specific cytotoxic T-lymphocytes by T cells, and the release of various cytokines in response to the recognition of an antigen (Dong, C. et al. (2003) “Immune Regulation by Novel Costimulatory Molecules,” Immunolog. Res. 28(1):39-48).
The ability of T cells to optimally mediate an immune response against an antigen requires two distinct signaling interactions (Viglietta, V. et al. (2007) “Modulating Co-Stimulation,” Neurotherapeutics 4:666-675; Korman, A. J. et al. (2007) “Checkpoint Blockade in Cancer Immunotherapy,” Adv. Immunol. 90:297-339). First, antigen that has been arrayed on the surface of antigen-presenting cells (APC) must be presented to an antigen-specific naive CD4+ T cell. Such presentation delivers a signal via the T cell receptor (TCR) that directs the T cell to initiate an immune response that will be specific to the presented antigen. Second, a series of co-stimulatory signals, mediated through interactions between the APC and distinct T cell surface molecules, triggers first the activation and proliferation of the T cells and ultimately their inhibition. Thus, the first signal confers specificity to the immune response whereas the second signal serves to determine the nature, magnitude and duration of the response.
The immune system is tightly controlled by co-stimulatory ligands and receptors. These molecules provide the second signal for T cell activation and provide a balanced network of positive and negative signals to maximize immune responses against infection while limiting immunity to self (Wang, L. et al. (Mar. 7, 2011) “VISTA, A Novel Mouse Ig Superfamily Ligand That Negatively Regulates T Cell Responses,” J. Exp. Med. 10.1084/jem.20100619:1-16; Lepenies, B. et al. (2008) “The Role Of Negative Costimulators During Parasitic Infections,” Endocrine, Metabolic & Immune Disorders—Drug Targets 8:279-288). Of particular importance is binding between the B7.1 (CD80) and B7.2 (CD86) ligands of the APC and the CD28 and CTLA-4 receptors of T-lymphocytes (Sharpe, A. H. et al. (2002) “The B7-CD28 Superfamily,” Nature Rev. Immunol. 2:116-126; Dong, C. et al. (2003) “Immune Regulation by Novel Costimulatory Molecules,” Immunolog. Res. 28(1):39-48; Lindley, P. S. et al. (2009) “The Clinical Utility Of Inhibiting CD28-Mediated Costimulation,” Immunol Rev. 229:307-321). Binding of B7.1 or of B7.2 to CD28 stimulates T cell activation; binding of B7.1 or B7.2 to CTLA4 inhibits such activation (Dong, C. et al. (2003) “Immune Regulation by Novel Costimulatory Molecules,” Immunolog. Res. 28(1):39-48; Lindley, P. S. et al. (2009) “The Clinical Utility Of Inhibiting CD28-Mediated Costimulation,” Immunol. Rev. 229:307-321; Greenwald, R. J. et al. (2005) “The B7 Family Revisited,” Ann. Rev. Immunol. 23:515-548). CD28 is constitutively expressed on the surface of T cells (Gross, J., et al. (1992) “Identification And Distribution Of The Costimulatory Receptor CD28 In The Mouse,” J. Immunol. 149:380-388), whereas CTLA4 expression is rapidly up-regulated following T-cell activation (Linsley, P. et al. (1996) “Intracellular Trafficking Of CTLA4 And Focal Localization Towards Sites Of TCR Engagement,” Immunity 4:535-543). Since CTLA4 is the higher affinity receptor (Sharpe, A. H. et al. (2002) “The B7-CD28 Superfamily,” Nature Rev. Immunol. 2:116-126), binding first initiates T cell proliferation (via CD28) and then inhibits it (via nascent expression of CTLA4), thereby dampening the effect when proliferation is no longer needed.
Further investigations into the ligands of the CD28 receptor have led to the identification and characterization of a set of related B7 molecules (the “B7 Superfamily”) (Coyle, A. J. et al. (2001) “The Expanding B7 Superfamily: Increasing Complexity In Costimulatory Signals Regulating T Cell Function,” Nature Immunol. 2(3):203-209; Sharpe, A. H. et al. (2002) “The B7-CD28 Superfamily,” Nature Rev. Immunol. 2:116-126; Greenwald, R. J. et al. (2005) “The B7 Family Revisited,” Ann. Rev. Immunol. 23:515-548; Collins, M. et al. (2005) “The B7 Family Of Immune-Regulatory Ligands,” Genome Biol. 6:223.1-223.7; Loke, P. et al. (2004) “Emerging Mechanisms Of Immune Regulation: The Extended B7 Family And Regulatory T Cells.” Arthritis Res. Ther. 6:208-214; Korman, A. J. et al. (2007) “Checkpoint Blockade in Cancer Immunotherapy,” Adv. Immunol. 90:297-339; Flies, D. B. et al. (2007) “The New B7s: Playing a Pivotal Role in Tumor Immunity,” J. Immunother. 30(3):251-260; Agarwal, A. et al. (2008) “The Role Of Positive Costimulatory Molecules In Transplantation And Tolerance,” Curr. Opin. Organ Transplant. 13:366-372; Lenschow, D. J. et al. (1996) “CD28/B7 System of T Cell Costimulation,” Ann. Rev. Immunol. 14:233-258; Wang, S. et al. (2004) “Co-Signaling Molecules Of The B7-CD28 Family In Positive And Negative Regulation Of T Lymphocyte Responses,” Microbes Infect. 6:759-766). There are at least eight members of the family: B7.1 (CD80), B7.2 (CD86), the inducible co-stimulator ligand (ICOS-L; B7-H2), the programmed cell death-1 ligand 1 (PD-L1; B7-H1), the programmed cell death-1 ligand 2 (PD-L2; B7-DC), B7-H3 (B7-RP2), B7-H4 (also referred to as B7x and B7S1; Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861; Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392; Prasad, D. V. et al. (2003) B7S1, A Novel B7 Family Member That Negatively Regulates T Cell Activation,” Immunity 18:863-873) and B7-H6 (Brandt, C. S. et al. (2009) “The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans”, J Exp Med. 206(7):1495-503).
Soluble forms of B7-CD28 family molecules are also implicated in the progression of rheumatoid diseases. Studies have shown that soluble PD-1 could be detected in rheumatoid arthritis (RA) patients and that the levels of soluble PD-1 correlated with TNF-α concentration in synovial fluid. Soluble B7-H4 (sH4) has been detected in ovarian cancer patients as a potential biomarker, and results from a study of 68 patients with RA and 24 healthy volunteers indicated that soluble B7-H4 was present in blood of 65% of patients with RA, compared with only 13% of healthy people (Simon, I. et al. (2006) “B7-H4 Is A Novel Membrane-Bound Protein And A Candidate Serum And Tissue Biomarker For Ovarian Cancer,” Cancer Res. 66(3):1570-1575, Azuma, T. et al. (2009) “Potential Role Of Decoy B7-H4 In The Pathogenesis Of Rheumatoid Arthritis: A Mouse Model Informed By Clinical Data,” PLoS Med., 6(10):e1000166). The levels of soluble B7-H4 were significantly higher in RA patients (96.1 ng/ml) relative to healthy people (<5 ng/ml).
In vivo studies in a murine model indicate that both overexpression of sH4 and deletion of B7-H4 caused inflammation (Azuma, T. et al. (2009) “Potential Role Of Decoy B7-H4 In The Pathogenesis Of Rheumatoid Arthritis: A Mouse Model Informed By Clinical Data,” PLoS Med. 6(10):e1000166). Symptoms in the mice appeared earlier and were more severe than controls, and inflammatory effects of soluble B7-H4 were shown to be dependent on neutrophils. Using a protein that mimics the normal signaling by B7-H4, disease development was prevented in the mice.
B. B7-H4
cDNA encoding the human B7-H4 protein was identified and cloned from placental cDNA (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861; Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392). B7-H4 is discussed in U.S. Pat. Nos. 7,931,896; 7,875,702; 7,847,081; 7,622,565; in United States Patent Publications No. 2011/0085970; 2011/0020325; 2010/0256000; 2010/0240585; 2010/0227343; 2010/0227335; 2010/0158936; 2010/0092524; 2010/0028450; 2009/0275633; 2009/0215084; 2009/0176317; 2009/0142342; 2009/0118175; 2009/0087416; 2009/0048122; 2009/0022747; 2009/0018315; 2008/0206235; 2008/0160036; 2008/0177039; 2008/0050370; 2007/0218032; 2007/0184473; 2007/0172504; 2007/0160578; 2007/0122378; 2007/0036783; 2006/0003452; in European Patent Publications Nos. EP 2124998 and EP 2109455; and in PCT Patent Publications WO 2011/026132A2; WO 2011/026122A2; WO 2011/005566A2; WO 2010/144295A1; WO 2010/102177A1; WO 2010/102167A1; WO 2009/111315A2; WO 2009/073533A2; WO 2008/092153A2; WO 2008/083239A2; WO 2008/083228A2; WO 2007/124361A2; WO 2007/122369A2; WO 2007/109254A2; WO 2007/087341A2; WO 2007/082154A2; WO 2007/067682A2; WO 2007/067681A2; WO 2007/041694A2; WO 2006/138670A2; WO 2006/133396A2; WO 2006/121991A2; WO 2006/066229A2; and WO 2006/007539A1.
Anti-B7-H4 antibodies are disclosed in U.S. Pat. Nos. 7,888,477; 7,737,255; 7,619,068; 6,962,980, and in United States Patent Publication No. 20080199461. WO/2013/025779 is of particular relevance.
Human B7-H4 protein possesses 282 amino acid residues, which have been categorized as including an amino terminal extracellular domain, a large hydrophobic transmembrane domain and a very short intracellular domain (consisting of only 2 amino acid residues). Like other B7 family members, B7-H4 possesses a pair of Ig-like regions in its extracellular domain. The B7-H4 protein has an overall structure of a type I transmembrane protein. The protein has minimal (about 25%) homology with other B7 family members (Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392).
The human B7-H4 cDNA sequence has been used to identify a murine B7-H4 homolog. The level of identity between the murine and human orthologs (approximately 87%) suggests that B7-H4 is highly conserved evolutionarily (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861; Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392). The extensive homology increases to 91% for the IgV domains of the proteins, which are believed to be involved in binding the B7-H4 receptor (Stamper, C. C. et al. (2001) “Crystal Structure Of The B7-1/CTLA-4 Complex That Inhibits Human Immune Responses,” Nature 410: 608-611; Schwartz, J. C. et al. (2001) “Structural Basis For Co-Stimulation By The Human CTLA-4/B7-2 Complex,” Nature 410:604-608).
In contrast to other B7 members, B7-H4 mRNA is widely expressed. Its expression has been found in the brain, heart, kidney, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, skin, small intestine, spleen, stomach, testis, thymus, thymus, and uterus (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861; Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392; Prasad, D. V. et al. (2003) B7S1, A Novel B7 Family Member That Negatively Regulates T Cell Activation,” Immunity 18:863-873; Prasad, D. V. et al. (2003) B7S1, A Novel B7 Family Member That Negatively Regulates T Cell Activation,” Immunity 18:863-873).
Despite the widespread expression of B7-H4 mRNA, the presence of B7-H4 protein on the surface of normal cells seems to be limited (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861; Choi, I. H. et al. (2003) “Genomic Organization And Expression Analysis Of B7-H4, An Immune Inhibitory Molecule Of The B7 Family,” J. Immunol. 171:4650-4654). Although freshly isolated human T cells, B cells, monocytes, and dendritic cells do not express B7-H4 on their cell surfaces (as determined via FACS analysis), its expression can be induced on such cells after in vitro stimulation lipopolysaccharides (LPS), phytohemagglutinin (PHA), gamma interferon (IFN-γ), phorbol 12-myristate 13-acetate (PMA), or ionomycin (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861). The finding of such a wide distribution of B7-H4 expression indicates that the function of B7-H4 is quite distinct from that of other inhibitory B7 molecules (see, Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392).
Consistent with this finding and the observation that the extracellular domain of B7-H4 has only about 25% amino acid homology with other B7 family members, B7-H4 does not bind to known B7 family receptors (i.e., CTLA-4, ICOS, PD-1 or CD28). Efforts to identify a B7-H4-specific receptor have revealed that such a receptor is expressed on activated T cells (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861). Binding of B7-H4 fusion protein to its putative receptor on T cells was found to significantly inhibit T cell proliferation and cytokine (IL-2 and IL-10) production and such inhibition was found to be non-reversible by CD28 costimulation (Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392; Prasad, D. V. et al. (2003) B7S1, A Novel B7 Family Member That Negatively Regulates T Cell Activation,” Immunity 18:863-873). B7-H4 has been found to arrest cell cycle progression of T cells in G0/G1 phase (Sica, G. L. et al. (2003) “B7-H4, A Molecule Of The B7 Family, Negatively Regulates T Cell Immunity,” Immunity 18:849-861) indicating that the protein mediates its inhibitory effects by arresting the cell cycle rather than by inducing apoptosis.
Anti-B7-H4 antibodies have been found to greatly increase the levels of IL-2 production by spleen cells in vitro, and to lead to a stronger immune response in vivo (Prasad, D. V. et al. (2003) B7S1, A Novel B7 Family Member That Negatively Regulates T Cell Activation,” Immunity 18:863-873; Zang, X. et al. (2003) B7x: A Widely Expressed B7 Family Member That Inhibits T Cell Activation,” Proc. Natl. Acad. Sci. (USA) 100:10388-10392; Prasad, D. V. et al. (2003) B7S1, A Novel B7 Family Member That Negatively Regulates T Cell Activation,” Immunity 18:863-873).
An absence of B7-H4 has been demonstrated to lead to resistance to Listeria monocytogenes infection through the direct regulation of the growth of neutrophil progenitors (Zhu, G. et al. (2009) “B7-H4 Deficient Mice Display Augmented Neutrophil-Mediated Innate Immunity,” Blood 113:1759-1769; Wei, J. et al. (2011) “Tissue-Specific Expression Of B7x Protects From CD4 T Cell-Mediated Autoimmunity,” J. Exper. Med. 208(8):1683-1694). As such B7-H4 has been proposed to play a role in immunity, especially autoimmunity and resistance to infection. Thus agonist anti-B7-H4 antibodies and soluble protein agonists of B7-H4 have been proposed for the treatment of inflammatory disorders (U.S. Pat. No. 7,931,896; United States Patent Publications Nos. 2007/0122378; 2008/0160036; 2009/0142342; and 2011/0020325; European Patent Publication No. EP 2124998; PCT Patent Publications Nos. WO 2006/133396; WO 2007/041694; WO 2008/083228; WO 2009/111315; WO 2010/144295; WO 2011/005566; WO 2011/026122; and WO 2011/026132).
The in vivo significance of B7-H4 is additionally demonstrated by the high levels of B7-H4 expression found in numerous tumor tissues, for example, human ovarian cancers (Choi, I. H. et al. (2003) “Genomic Organization And Expression Analysis Of B7-H4, An Immune Inhibitory Molecule Of The B7 Family,” J. Immunol. 171:4650-4654; Kryczek, I. et al. (2006) “B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma,” J. Exp. Med. 203(4):871-881; Bignotti, E. et al. (2006) “Differential Gene Expression Profiles Between Tumor Biopsies And Short Term Primary Cultures Of Ovarian Serous Carcinomas: Identification Of Novel Molecular Biomarkers For Early Diagnosis And Therapy,” Gynecol. Oncol. 103:405-416; Tringler, B. et al. (2006) “B7-H4 Overexpression In Ovarian Tumors,” Gynecol. Oncol. 100:44-52; Simon, I. et al. (2006) “B7-h4 Is A Novel Membrane-Bound Protein And A Candidate Serum And Tissue Biomarker For Ovarian Cancer,” Cancer Res. 66:1570-1575; Salceda, S. et al. (2005) “The Immunomodulatory Protein B7-H4 Is Overexpressed In Breast And Ovarian Cancers And Promotes Epithelial Cell Transformation,” Exp. Cell Res. 306:128-141), non-small-cell lung cancer (Sun, Y. et al. (2006) “B7-H3 And B7-H4 Expression In Non-Small-Cell Lung Cancer,” Lung Cancer 53:143-151), ductal and lobular breast cancer (Salceda, S. et al. (2005) “The Immunomodulatory Protein B7-H4 Is Overexpressed In Breast And Ovarian Cancers And Promotes Epithelial Cell Transformation,” Exp. Cell Res. 306:128-141; Tringler, B. et al. (2005) “B7-H4 Is Highly Expressed In Ductal And Lobular Breast Cancer,” Clin. Cancer Res. 11:1842-1848), and renal cell carcinoma (Krambeck, A. E. et al. (2006) “B7-H4 Expression In Renal Cell Carcinoma And Tumor Vasculature: Associations With Cancer Progression And Survival,” Proc. Natl. Acad. Sci. (USA) 103:10391-10396). The expression of B7-H4 on tumor cells has been found to correlate with adverse clinical and pathologic features, including tumor aggressiveness (Krambeck, A. E. et al. (2006) “B7-H4 Expression In Renal Cell Carcinoma And Tumor Vasculature: Associations With Cancer Progression And Survival,” Proc. Natl. Acad. Sci. (U.S.A.) 103(2): 10391-10396).
C. Tumor-Associated Macrophages (TAMs)
The association between inflammation and cancer dates back more than a century to observations noting infiltration of large numbers of white blood cells into tumor sites (Balkwill, F. et al. (2001) “Inflammation And Cancer: Back To Virchow?,” Lancet 357:539-545; Coussens, L. M. et al. (2002) “Inflammation and Cancer,” Nature 420:860-867). Several studies have now identified two main pathways linking inflammation and cancer: an intrinsic and an extrinsic pathway (Allavena, P. et al. (2008) “Pathways Connecting Inflammation and Cancer,” Curr. Opin. Genet. Devel. 18:3-10; Colotta, F. (2009) “Cancer-Related Inflammation, The Seventh Hallmark of Cancer: Links to Genetic Instability,” Carcinogenesis 30(7): 1073-1081; Porta, C. et al. (2009) “Cellular and Molecular Pathways Linking Inflammation and Cancer,” Immunobiology 214:761-777). The intrinsic pathway includes genetic alterations that lead to inflammation and carcinogenesis, whereas the extrinsic pathway is characterized by microbial/viral infections or autoimmune diseases that trigger chronic inflammation in tissues associated with cancer development. Both pathways activate pivotal transcription factors of inflammatory mediators (e.g., NF-κB, STAT3, and HIF-1) and result in the recruitment of leukocytes that play a key role in inflammation (Solinas, G. et al. (2009) “Tumor-Associated Macrophages (TAM) As Major Players Of The Cancer-Related Inflammation,” J. Leukoc. Biol. 86(5):1065-1073).
TAMs provide a link between inflammation and cancer. Macrophages are immune system cells derived from activated blood monocytes. They are primarily recognized as participating in inflammatory responses induced by pathogens or tissue damage by acting to remove (i.e., phagocytose) pathogens, dead cells, cellular debris, and various components of the extra-cellular matrix (ECM). Macrophages have been found to constitute an important constituent in the tumor microenvironment and to represent up to 50% of the tumor mass.
In addition to mediating phagocytosis, macrophages secrete pro-angiogenic growth factors and matrix-remodeling proteases, and thus play a role in the development of the vascular infrastructure (i.e., angiogenesis) needed for tumor development and growth (Pollard, J. W. (2009) “Trophic Macrophages In Development And Disease,” Nat. Rev. Immunol. 9:259-270). As such, the presence of macrophages within a tumor appears to assist the growth of the tumor. A number of studies provide evidence that the presence of tumor-associated macrophages within the tumor is a negative prognostic factor of survival (Farinha, P. et al. (2005) “Analysis Of Multiple Biomarkers Shows That Lymphoma-Associated Macrophage (LAM) Content Is An Independent Predictor Of Survival In Follicular Lymphoma (FL),” Blood 106:2169-2174; Dave, S. S. et al. (2004) “Prediction Of Survival In Follicular Lymphoma Based On Molecular Features Of Tumor-Infiltrating Immune Cells,” N. Engl. J. Med. 351:2159-2169; Solinas, G. et al. (2009) “Tumor-Associated Macrophages (TAM) As Major Players Of The Cancer-Related Inflammation,” J. Leukoc. Biol. 86(5):1065-1073).
Incipient tumors need to generate their own vasculature to enable oxygen and nourishment delivery to the expanding tumor cells. Thus, the progression of tumors requires coordinated signaling between tumor cells and non-malignant cells in the tumor microenvironment (Kaler, P. et al. (2010) “Tumor Associated Macrophages Protect Colon Cancer Cells from TRAIL-Induced Apoptosis through IL-1β-Dependent Stabilization of Snail in Tumor Cells,” PLos ONE 5(7):e11700 1-13). It is now well established that TAMs, as well as neutrophils, fibroblasts and other cells cooperate with tumor cells to facilitate angiogenesis in tumors (Nucera, S. et al. (2011) “The Interplay Between Macrophages And Angiogenesis In Development, Tissue Injury And Regeneration,” Int. J. Dev. Biol. doi: 10.1387/ijdb.103227sn; Zamarron, B. F. et al. (2011) “Dual Roles Of Immune Cells And Their Factors In Cancer Development And Progression,” Int. J. Biol. Sci. 7(5):651-658; Liu, J. et al. (2011) “Tumor-Associated Macrophages Recruit CCR6+ Regulatory T Cells And Promote The Development Of Colorectal Cancer Via Enhancing CCL20 Production In Mice,” PLoS One. 6(4):e19495; Rigo, A. et al. (2010) “Macrophages May Promote Cancer Growth Via A GM-CSF/HB-EGF Paracrine Loop That Is Enhanced By CXCL12,” Molec. Cancer 9(273):1-13; Lin, J. Y. et al. (2011) “Clinical Significance Of Tumor-Associated Macrophage Infiltration In Supraglottic Laryngeal Carcinoma,” Chin. J. Cancer 30(4):280-286; Vergati, M. (2011) “The Consequence Of Immune Suppressive Cells In The Use Of Therapeutic Cancer Vaccines And Their Importance In Immune Monitoring,” J. Biomed. Biotechnol. 2011:182413).
B7-H4 has been shown to be over-expressed in TAMs including those present in ovarian tumors (Kryczek, I. et al. (2006) “B7-H4 Expression Identifies A Novel Suppressive Macrophage Population In Human Ovarian Carcinoma,” J. Exp. Med. 203(4):871-881; Kryczek, I. et al. (2007) “Relationship Between B7-H4, Regulatory T Cells, And Patient Outcome In Human Ovarian Carcinoma,” Cancer Res. 67(18):8900-8905).
Despite all prior advances in the treatment of inflammation and cancer, a need remains for improved compositions capable of providing enhanced immunotherapy for the treatment of cancer. Therefore, compositions and their use to treat cancer and other diseases and conditions are provided.
It is an object of the invention to provide compositions and methods for inducing surface B7-H4 internalization to suppress B7-H4 mediated immune evasion for a treatment of cancer, or bacteria or viral infections.
It is another object of the invention to provide compositions and methods for B7-H4 mAb-payload drug-conjugate to target B7-H4 positive tumors for a treatment of cancer.